OP0128 PHARMACOKINETICS AND PHARMACODYNAMICS OF METHOTREXATE POLYGLUTAMATE IN PATIENTS WITH RHEUMATOID ARTHRITIS TREATED WITH LOW OR HIGH DOSE-METHOTREXATE IN COMBINATION WITH ADALIMUMAB: RESULTS FROM THE MIRACLE TRIAL
Authors: H. Tamai, K. Ikeda, T. Miyamoto, H. Taguchi, C. F. Kuo, K. Shin, S. Hirata, Y. Okano, S. Sato, H. Yasuoka, I. A. Choi, S. H. Park, M. Y. Weng, M. Kuwana, Y. J. Lee, T. Ishii, J. Kim, H. Kameda, T. Kojima, H. J. Baek, P. N. Hsu, C. M. Huang, T. T. Cheng, W. Y. Sung, W. C. Tsai, T. Taninaga, M. Mori, H. Miyagishi, Y. Sato, T. Takeuchi, Y. Kaneko
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Concentrations of methotrexate polyglutamates (MTX-PGs) in erythrocytes have been reported to be associated with efficacy and safety in patients with rheumatoid arthritis (RA) treated with MTX. However, little is known about the pharmacokinetics and pharmacodynamics of MTX-PG concentrations and their relationship with disease control and adverse effects in patients treated with MTX and a tumor necrosis factor inhibitor (TNFi), especially in patients whose MTX dose is reduced at TNFi initiation. <h3>Objectives</h3> To clarify the association between the concentrations of MTX-PGs with efficacy and safety of treatment in patients with RA treated with low dose MTX and high dose MTX in combination with adalimumab, a TNFi. <h3>Methods</h3> The MIRACLE study (NCT03505008) was a multinational, randomized study in patients with RA with inadequate response to MTX. Three hundred MTX-naive patients were enrolled in the study and started and increased MTX to the maximum tolerable dose. Patients who did not achieve remission according to simplified disease activity index (SDAI) at week 24 were randomised to the maximum tolerable dose group or the reduced dose group and started subcutaneous adalimumab 40 mg every other week. We measured the concentrations of MTX-PGs in erythrocytes with liquid chromatograph mass spectrometry at weeks 0, 4, 8, 12, 24, 36, and 48 and analysed the association between the concentration of MTX-PGs with the efficacy and safety of adalimumab. <h3>Results</h3> The previously reported results of the MIRACLE trial showed that the efficacy of adalimumab with reduced dose of concomitant MTX was not inferior to that with maximum tolerable dose of MTX (remission rates at week 48: 44.8 % vs 38.4 %, respectively) with better safety profile (adverse events: 19.7% vs 35.3%, respectively). In the maximum tolerable dose group, MTX dose was 13.5± 3.2 mg/week (0.24± 0.1 mg/kg/week) at week 24 and maintained the dose through 48 weeks. In the reduced dose group, MTX dose was reduced from 12.6± 3.1 mg/week (0.23± 0.1 mg/kg/week) to 7.6± 0.5 mg/week (0.14± 0.0 mg/kg/week) at week 24. The concentration of total MTX-PGs in the maximum tolerable dose group was 109.5± 36.7 nmol/L, 99.9± 40.1 nmol/L, and 96.4± 38.3 nmol/L at weeks 24, 36, and 48, respectively. In the reduced dose group, total MTX-PGs concentration was decreased from 113.5± 55.3 nmol/L at week 24 to 80.7± 53.1 nmol/L at week 36 and 68.9± 54.4 nmol/L at week 48 (Figure 1). The decrease in individual MTX-PG levels were more prominent in long and very long chain MTX-PGs compared with short chains; MTX-PG 1-2, 59.0± 44.7 nmol/L at week 24 to 48.9± 43.8 nmol/L at week 36; MTX PG 3-5, 54.5± 28.8 nmol/L at week 24 to 31.8± 18.7 nmol/L at week 36. In both groups, MTX-PG concentrations at week 48 were not different between patients who achieved SDAI remission and those who did not (95.1 nmol/L vs 98.6 nmol/L in the maximum tolerable dose group, p=0.743; 64.3 nmol/L vs 72.9 nmol/L in the reduced dose group, p=0.556, respectively). On the other hand, patients n the reduced dose group who experienced adverse events after week 24 tended to have higher concentartion of total MTX-PGs than those who did not (140.3 nmol/L vs 106.9 nmol/L at week 24, p=0.050; 97.3 nmol/L vs 63.0 nmol/L at week 48, p=0.069, respectively). <h3>Conclusion</h3> The MIRACLE randomised study demonstrated that total MTX-PG concentrations were not relevant for SDAI remission achievement by combined treatment with methotrexate and adalimumab while patients who experienced adverse events were exposed to higher MTX-PG concentrations. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Hiroya Tamai Speakers bureau: AbbVie, Eisai, Grant/research support from: Eisai, Kei Ikeda Speakers bureau: Abbvie, Asahi-Kasei, Astellas, Bristol-Myers Suibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Mitsubishi-Tanabe, Gilead, UCB, Grant/research support from: Mitsubishi-Tanabe, Toshiaki Miyamoto Speakers bureau: AbbVie, Astellas, AstraZeneca, Bristol Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Kirin, Pfizer, UCB, Hiroaki Taguchi: None declared, Chang-Fu Kuo: None declared, Kichul Shin Consultant of: KD Bio, Grant/research support from: AbbVie, Astellas, Bristol Myers Squibb, Yuhan, Shintaro Hirata Speakers bureau: AbbVie, Asahi-Kasei, Astellas, Ayumi, Bristol Myers Squibb, Celgene, Chugai, Eisai, Eli Lilly, Gilead, Glaxo SmithKline, Janssen, Kyorin, Mitsubishi-Tanabe, Novartis, Pfizer, Sanofi, UCB, Paid instructor for: AbbVie, Mitsubishi-Tanabe, Consultant of: AbbVie, Astellas, Bristol Myers Squibb, Eisai, Gilead, Eli Lilly, Grant/research support from: AbbVie, Asahi-Kasei, Chugai, Eisai, Eli Lilly, Mitsubishi-Tanabe, Otsuka, Pfizer, Sanofi, Shionogi, UCB, yutaka okano: None declared, Shinji Sato Grant/research support from: AbbVie, Asahi Kasei, Ayumi, Chugai, Diichi Sankyo, Eisai, Eli Lilly, Teijin, Pfizer, Hidekata Yasuoka Speakers bureau: AbbVie, Boehringer-Ingelheim, Gilead, Janssen, Nippon shinyaku, Grant/research support from: Asahi Kasei, Chugai, Eisai, Mitsubishi-Tanabe, Taisho, In Ah Choi Speakers bureau: AbbVie, Eisai, Sung-Hwan Park: None declared, Meng-Yu Weng Paid instructor for: Novartis, Eli Lilly, Chugai, AbbVie, Consultant of: AbbVie, Masataka Kuwana Speakers bureau: AbbVie, Asahi Kasei, Astellas, Boehringer Ingelheim, Chugai, Nippon Shinyaku, Mitsubishi-Tanabe, Consultant of: Boehringer Ingelheim, Kissei, Mochida, Grant/research support from: Boehringer Ingelheim, Ono, MBL, Yun Jong Lee Grant/research support from: Yuhan, Tomonori Ishii Speakers bureau: AbbVie, Asahi Kasei, Astellas, Boehringer Ingelheim, Bristol-Myers Suibb, Chugai, Eisai, Eli Lilly, Gilead, Glaxo Smith Kline, Janssen, Novartis, Pfizer, Jinhyun Kim: None declared, Hideto Kameda Speakers bureau: AbbVie, Asahi Kasei, Astellas, Boehringer, Bristol-Myers, Chugai, Eisai, Eli Lilly, Gilead, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer, UCB, Grant/research support from: AbbVie, Asahi Kasei, Boehringer, Chugai, Eisai, Mitsubishi-Tanabe, Taisho, Toshihisa Kojima Speakers bureau: AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Pfizer, Taisho, UCB, Han Joo Baek: None declared, Ping-Ning Hsu: None declared, Chun-Ming Huang Paid instructor for: AbbVie, Pfizer, Tien-Tsai Cheng Paid instructor for: AbbVie, Grant/research support from: AbbVie, Wan-Yu Sung: None declared, Wen-Chan Tsai: None declared, Takehiro Taninaga Shareholder of: Eisai, Employee of: Eisai, Masahiko Mori Shareholder of: Eisai, Employee of: Eisai, Hideaki Miyagishi Shareholder of: Eisai, Employee of: Eisai, Yasunori Sato Speakers bureau: Eisai, Kowa, Consultant of: Mochida, Tsutomu Takeuchi Speakers bureau: AbbVie, Asahi Kasei, Astellas, Bristol-Myers Squibb, Chugai, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Mitsubishi-Tanabe, Pfizer, Consultant of: AbbVie, Chugai, Eli Lilly, Gilead, Mitsubishi-Tanabe, Grant/research support from: AbbVie, Asahi Kasei, Ayumi, Chugai, Eisai, Eli Lilly, Mitsubishi-Tanabe, Ono, Yuko Kaneko Speakers bureau: AbbVie, Asahi Kasei, Astellas, Boehringer Ingelheim, Bristol Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly, Gilead, Janssen, Mitsubishi-Tanabe, Novartis, Pfizer, Grant/research support from: AbbVie,Asahi Kasei, Ayumi, Boehringer Ingelheim, Chugai, Eisai, Mitsubishi-Tanabe.